TY - JOUR
T1 - Environmental neurotoxicants and inflammasome activation in Parkinson's disease – A focus on the gut-brain axis
AU - Johnson, Aishwarya M.
AU - Ou, Zhen Yi Andy
AU - Gordon, Richard
AU - Saminathan, Hariharan
N1 - Funding Information:
RG is supported by an Advance Queensland Mid-Career Fellowship and research grants from the Michael J Fox Foundation and the Shake It Up Australia Foundation. HS is supported by United Arab University Grants - UAE-Research Start-Up 31F129 .
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2022/1
Y1 - 2022/1
N2 - Inflammasomes are multi-protein complexes expressed in immune cells that function as intracellular sensors of environmental, metabolic and cellular stress. Inflammasome activation in the brain, has been shown to drive neuropathology and disease progression by multiple mechanisms, making it one of the most attractive therapeutic targets for disease modification in Parkinson's Disease (PD). Extensive inflammasome activation is evident in the brains of people with PD at the sites of dopaminergic degeneration and synuclein aggregation. While substantial progress has been made on validating inflammasome activation as a therapeutic target for PD, the mechanisms by which inflammasome activation is triggered and sustained over the disease course remain poorly understood. A growing body of evidence point to environmental and occupational chemical exposures as possible triggers of inflammasome activation in PD. The involvement of the gastrointestinal system and gut microbiota in PD pathophysiology is beginning to be elucidated, especially the profound link between gut dysbiosis and immune activation. While large cohort studies confirmed specific changes in the gut microbiota in PD patients compared to age-matched healthy controls, recent research suggest that synuclein pathology could be initiated in the gastrointestinal tract. In this review, we present a summarized perspective on current understanding on inflammasome activation and the gut-brain-axis link during PD pathophysiology. We discuss multiple environmental toxicants that are implicated as the etiological agents in causing idiopathic PD and their mechanistic underpinnings during neuroinflammatory events. We additionally present future directions that needs to address the research questions related to the gut-microbiome-brain mechanisms in PD.
AB - Inflammasomes are multi-protein complexes expressed in immune cells that function as intracellular sensors of environmental, metabolic and cellular stress. Inflammasome activation in the brain, has been shown to drive neuropathology and disease progression by multiple mechanisms, making it one of the most attractive therapeutic targets for disease modification in Parkinson's Disease (PD). Extensive inflammasome activation is evident in the brains of people with PD at the sites of dopaminergic degeneration and synuclein aggregation. While substantial progress has been made on validating inflammasome activation as a therapeutic target for PD, the mechanisms by which inflammasome activation is triggered and sustained over the disease course remain poorly understood. A growing body of evidence point to environmental and occupational chemical exposures as possible triggers of inflammasome activation in PD. The involvement of the gastrointestinal system and gut microbiota in PD pathophysiology is beginning to be elucidated, especially the profound link between gut dysbiosis and immune activation. While large cohort studies confirmed specific changes in the gut microbiota in PD patients compared to age-matched healthy controls, recent research suggest that synuclein pathology could be initiated in the gastrointestinal tract. In this review, we present a summarized perspective on current understanding on inflammasome activation and the gut-brain-axis link during PD pathophysiology. We discuss multiple environmental toxicants that are implicated as the etiological agents in causing idiopathic PD and their mechanistic underpinnings during neuroinflammatory events. We additionally present future directions that needs to address the research questions related to the gut-microbiome-brain mechanisms in PD.
KW - Chemical exposures
KW - Gut-brain axis
KW - Inflammasome activation
KW - Inflammation
KW - Microbiome
KW - Neurotoxicants
KW - Parkinson's disease
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U2 - 10.1016/j.biocel.2021.106113
DO - 10.1016/j.biocel.2021.106113
M3 - Review article
C2 - 34737076
AN - SCOPUS:85123025282
SN - 1357-2725
VL - 142
JO - International Journal of Biochemistry and Cell Biology
JF - International Journal of Biochemistry and Cell Biology
M1 - 106113
ER -